Ultraviolet (UV) radiation is a major environmental carcinogen and the primary cause of non-melanoma skin cancer. UV radiation is also immunosuppressive and the systemic immune suppression induced by UV exposure is a major risk factor for skin cancer induction. Previous findings from my lab have indicated that UV exposure activates a cytokine cascade (UV? PAF?PGE2 ?IL-4, ?IL-10? suppressed dendritic cell IL-12 production) that leads to systemic immune suppression. Because mast cells release many of the factors known to play a role in UV-induced systemic immune suppression, we focused on their role in the induction of immune suppression to gain a better understanding of the mechanisms involved. Mast cells clearly play an essential role in UV-induced immune suppression because UV does not induce immune suppression in mast cell deficient mice. Conventional wisdom suggests mast cell migrate to sites of inflammation where they release a variety of immune modulatory mediators that affect immune function. We observed that UV radiation activates mast cell migration from the site of inflammation (skin) to the draining lymph nodes. When this "reverse mast cell migration" was inhibited by blocking CXCR4 binding to its ligand CXCL12, an interaction known to induce mast cell migration, immune suppression was ablated. This suggests that unconventional mast cell migration from the skin to the lymph nodes is critically important for the induction of immune suppression and sunlight-induced skin carcinogenesis. The goal of the experiments outlined in this proposal is to test this hypothesis. Four specific aims will be examined to provide data to support the hypothesis. Specific Aim #1 will focus on providing additional data to support the hypothesis that the migration of dermal mast cells from the skin to the draining lymph node is an essential step in the activation of immune suppression. Specific Aim #2 will focus on determining the mechanisms responsible for reverse mast cell migration. Specific Aim #3 will focus on determining how mast cells mediate immune suppression in the lymph nodes. Specific Aim #4 will examine the role of mast cells in UV-induced skin cancer induction. The long-term goal of my research is to determine the mechanism(s) underlying UV-induced immune suppression in order to provide insights in the development of new therapeutic reagents for skin cancer. Targeting mast cell migration may provide a new therapeutic target to prevent sunlight-induced skin cancer. In addition, preliminary data generated in my lab indicates that the immune suppression induced by treating the skin with other immunosuppressants (psoralen plus UVA and/or the dermal application of jet fuel) is mast cell dependent and activates reverse mast cell migration. This suggests that the data generated during the course of this proposal may have broad implications in regard to the mechanisms by which environmental immunosuppressants interact with the immune system to down-regulate its function. PUBLIC HEALTH RELEVANCE: The primary agent responsible for inducing skin cancer, the most prevalent form of human cancer, is the ultraviolet (UV) radiation in sunlight. UV radiation is also immune suppressive, and a variety of studies have shown that the immune suppression induced by sunlight is a major risk factor for skin cancer induction. The long term goal of my research is to gain a better understanding of the mechanisms underlying UV-induced immune suppression and skin cancer induction in order to develop new and novel therapeutic agents to prevent sunlight-induced skin cancer induction.